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Cited by 72Parkinson's Disease Mechanisms and TreatmentsAutophagy in Disease and TherapyATP Synthase and ATPases Research

Parkinson’s disease-associated ATP13A2/PARK9 functions as a lysosomal H+,K+-ATPase

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Fujii, Takuto, Nagamori, Shushi, Wiriyasermkul, Pattama, Zheng, Shizhou, Yago, Asaka, Shimizu, Takahiro, Tabuchi, Yoshiaki, Okumura, Tomoyuki +3 more·2023·Nature Communications
DOI 10.1038/s41467-023-37815-zPMC PMC10119128
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Abstract

Mutations in the human ATP13A2 (PARK9), a lysosomal ATPase, cause Kufor-Rakeb Syndrome, an early-onset form of Parkinson’s disease (PD). Here, we demonstrate that ATP13A2 functions as a lysosomal H + ,K + -ATPase. The K + -dependent ATPase activity and the lysosomal K + -transport activity of ATP13A2 are inhibited by an inhibitor of sarco/endoplasmic reticulum Ca 2+ -ATPase, thapsigargin, and K + -competitive inhibitors of gastric H + ,K + -ATPase, such as vonoprazan and SCH28080. Interestingly, these H + ,K + -ATPase inhibitors cause lysosomal alkalinization and α-synuclein accumulation, which are pathological hallmarks of PD. Furthermore, PD-associated mutants of ATP13A2 show abnormal expression and function. Our results suggest that the H + /K + -transporting function of ATP13A2 contributes to acidification and α-synuclein degradation in lysosomes.

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  • In yeast and C. elegans, lysosomal pH becomes more alkaline with age.

    “In yeast and C. elegans, lysosomal pH becomes more alkaline with age.56,57”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [56]

    The Results section reports lysosomal alkalinization after ATP13A2 inhibition in human cells, not a change with age in yeast or C. elegans. Searches for yeast, C. elegans, aging, and lysosomal pH found no passage in our copy addressing the attributed claim; page numbers were unavailable. (LLM, conf=0.77)

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  1. [1]Chu Y-T Tai C-H Lin C-H Wu R-M Updates on the genetics of Parkinson’s disease: clinical implications and future treatment Acta Neurol. Taiwan. 2021 30 83 93 34841503
  2. [2]Srinivasan E Alpha-synuclein aggregation in Parkinson’s disease Front. Med. 2021 8 736978 10.3389/fmed.2021.736978 PMC8558257 34733860 · DOI
  3. [3]Yang X Xu Y Mutations in the ATP13A2 gene and Parkinsonism: a preliminary review Biomed. Res. Int. 2014 2014 371256 10.1155/2014/371256 25197640 PMC4147200 · DOI
  4. [4]Park J-S Blair NF Sue CM The role of ATP13A2 in Parkinson’s disease: clinical phenotypes and molecular mechanisms Mov. Disord. 2015 30 770 779 10.1002/mds.26243 25900096 · DOI · Paper page
  5. [5]Li W Fu Y Halliday GM Sue CM PARK genes link mitochondrial dysfunction and alpha-synuclein pathology in sporadic Parkinson’s disease Front. Cell Dev. Biol. 2021 9 612476 10.3389/fcell.2021.612476 34295884 PMC8291125 · DOI
  6. [6]Ramonet D PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity Hum. Mol. Genet. 2012 21 1725 1743 10.1093/hmg/ddr606 22186024 PMC3465694 · DOI
  7. [7]Usenovic M Tresse E Mazzulli JR Taylor JP Krainc D Deficiency of ATP13A2 leads to lysosomal dysfunction, α-synuclein accumulation, and neurotoxicity J. Neurosci. 2012 32 4240 4246 10.1523/JNEUROSCI.5575-11.2012 22442086 PMC3462811 · DOI
  8. [8]Palmgren MG Nissen P P-type ATPases Annu. Rev. Biophys. 2011 40 243 266 10.1146/annurev.biophys.093008.131331 21351879 · DOI
  9. [9]Dehay B Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration Proc. Natl. Acad. Sci. USA 2012 109 9611 9616 10.1073/pnas.1112368109 22647602 PMC3386132 · DOI
  10. [10]Lopes da Fonseca T Pinho R Outeiro TF A familial ATP13A2 mutation enhances alpha-synuclein aggregation and promotes cell death Hum. Mol. Genet. 2016 25 2959 2971 27282395
  11. [11]Thomas T Thomas TJ Polyamine metabolism and cancer J. Cell. Mol. Med. 2003 7 113 126 10.1111/j.1582-4934.2003.tb00210.x 12927050 PMC6740079 · DOI
  12. [12]van Veen S ATP13A2 deficiency disrupts lysosomal polyamine export Nature 2020 578 419 424 10.1038/s41586-020-1968-7 31996848 · DOI
  13. [13]Li P Wang K Salustros N Grønberg C Gourdon P Structure and transport mechanism of P5B-ATPases Nat. Commun. 2021 12 1 8 34172751 PMC8233418
  14. [14]Antony T Cellular polyamines promote the aggregation of alpha-synuclein J. Biol. Chem. 2003 278 3235 3240 10.1074/jbc.M208249200 12435752 · DOI
  15. [15]Si J ATP13A2 regulates cellular α-synuclein multimerization, membrane association, and externalization Int. J. Mol. Sci. 2021 22 2689 10.3390/ijms22052689 33799982 PMC7962109 · DOI
  16. [16]Sim SI von Bülow S Hummer G Park E Structural basis of polyamine transport by human ATP13A2 (PARK9) Mol. Cell 2021 81 4635 4649.e8 10.1016/j.molcel.2021.08.017 34715013 PMC8604775 · DOI
  17. [17]Tillinghast J Drury S Bowser D Benn A Lee KPK Structural mechanisms for gating and ion selectivity of the human polyamine transporter ATP13A2 Mol. Cell 2021 81 4650 4662.e4 10.1016/j.molcel.2021.10.002 34715014 · DOI
  18. [18]Chen X Cryo-EM structures and transport mechanism of human P5B type ATPase ATP13A2 Cell Discov. 2021 7 106 10.1038/s41421-021-00334-6 34728622 PMC8564547 · DOI
  19. [19]Tomita A Cryo-EM reveals mechanistic insights into lipid-facilitated polyamine export by human ATP13A2 Mol. Cell 2021 81 4799 4809.e5 10.1016/j.molcel.2021.11.001 34798056 PMC7612442 · DOI
  20. [20]Holemans T A lipid switch unlocks Parkinson’s disease-associated ATP13A2 Proc. Natl. Acad. Sci. USA 2015 112 9040 9045 10.1073/pnas.1508220112 26134396 PMC4517210 · DOI
  21. [21]Gitler AD Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity Nat. Genet. 2009 41 308 315 10.1038/ng.300 19182805 PMC2683786 · DOI
  22. [22]Tan J Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein J. Biol. Chem. 2011 286 29654 29662 10.1074/jbc.M111.233874 21724849 PMC3191006 · DOI
  23. [23]Kong SMY Parkinson’s disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-Synuclein externalization via exosomes Hum. Mol. Genet. 2014 23 2816 2833 10.1093/hmg/ddu099 24603074 · DOI
  24. [24]Tsunemi T Krainc D Zn2+ dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulation Hum. Mol. Genet. 2014 23 2791 2801 10.1093/hmg/ddt572 24334770 PMC4014186 · DOI
  25. [25]Tsunemi T Increased lysosomal exocytosis induced by lysosomal Ca2+ channel agonists protects human dopaminergic neurons from α-synuclein toxicity J. Neurosci. 2019 39 5760 5772 10.1523/JNEUROSCI.3085-18.2019 31097622 PMC6636071 · DOI
  26. [26]Wang X TPC proteins are phosphoinositide-activated sodium-selective ion channels in endosomes and lysosomes Cell 2012 151 372 383 10.1016/j.cell.2012.08.036 23063126 PMC3475186 · DOI
  27. [27]Djarmati A ATP13A2 variants in early-onset Parkinson’s disease patients and controls Mov. Disord. 2009 24 2104 2111 10.1002/mds.22728 19705361 · DOI
  28. [28]Fujii T Inhibition of gastric H+,K+-ATPase by new dihydropyrazole derivative KYY-008 Biochem. Biophys. Res. Commun. 2021 567 177 182 10.1016/j.bbrc.2021.06.056 34166915 · DOI
  29. [29]Inatomi N Matsukawa J Sakurai Y Otake K Potassium-competitive acid blockers: Advanced therapeutic option for acid-related diseases Pharmacol. Ther. 2016 168 12 22 10.1016/j.pharmthera.2016.08.001 27514776 · DOI
  30. [30]Ward RM Kearns GL Proton pump inhibitors in pediatrics: mechanism of action, pharmacokinetics, pharmacogenetics, and pharmacodynamics Paediatr. Drugs 2013 15 119 131 10.1007/s40272-013-0012-x 23512128 PMC3616221 · DOI
  31. [31]Morii M Takata H Takeguchi N Acid activation of omeprazole in isolated gastric vesicles, oxyntic cells, and gastric glands Gastroenterology 1989 96 1453 1461 10.1016/0016-5085(89)90512-X 2541041 · DOI
  32. [32]Hersey SJ Perez A Matheravidathu S Sachs G Gastric H+-K+-ATPase in situ: evidence for compartmentalization Am. J. Physiol. 1989 257 G539 G547 2552824
  33. [33]Asano S Furumoto R Tega Y Matsuda S Takeguchi N Mutational analysis of the putative K+-binding site on the fourth transmembrane segment of the gastric H+,K+-ATPase J. Biochem. 2000 127 993 1000 10.1093/oxfordjournals.jbchem.a022716 10833267 · DOI
  34. [34]Xicoy H Wieringa B Martens GJM The SH-SY5Y cell line in Parkinson’s disease research: a systematic review Mol. Neurodegener. 2017 12 10 10.1186/s13024-017-0149-0 28118852 PMC5259880 · DOI · Paper page
  35. [35]Dehay B Lysosomal dysfunction in Parkinson disease: ATP13A2 gets into the groove Autophagy 2012 8 1389 1391 10.4161/auto.21011 22885599 PMC3442887 · DOI
  36. [36]Tsunemi T Hamada K Krainc D ATP13A2/PARK9 regulates secretion of exosomes and α-synuclein J. Neurosci. 2014 34 15281 15287 10.1523/JNEUROSCI.1629-14.2014 25392495 PMC4228131 · DOI
  37. [37]Fujiwara H alpha-Synuclein is phosphorylated in synucleinopathy lesions Nat. Cell Biol. 2002 4 160 164 10.1038/ncb748 11813001 · DOI
  38. [38]Lee BR Matsuo Y Cashikar AG Kamitani T Role of Ser129 phosphorylation of α-synuclein in melanoma cells J. Cell Sci. 2013 126 696 704 10.1242/jcs.122093 23203798 PMC3613186 · DOI
  39. [39]Terada M The effect of truncation on prion-like properties of α-synuclein J. Biol. Chem. 2018 293 13910 13920 10.1074/jbc.RA118.001862 30030380 PMC6130941 · DOI
  40. [40]Saito Y Accumulation of phosphorylated α-synuclein in aging human brain J. Neuropathol. Exp. Neurol. 2003 62 644 654 10.1093/jnen/62.6.644 12834109 · DOI
  41. [41]Delic V Sensitivity and specificity of phospho-Ser129 α-synuclein monoclonal antibodies J. Comp. Neurol. 2018 526 1978 1990 10.1002/cne.24468 29888794 PMC6031478 · DOI · Paper page
  42. [42]Nonaka T Watanabe ST Iwatsubo T Hasegawa M Seeded aggregation and toxicity of α-synuclein and tau: cellular models of neurodegenerative diseases J. Biol. Chem. 2010 285 34885 34898 10.1074/jbc.M110.148460 20805224 PMC2966103 · DOI
  43. [43]Guan H Mitochondrial ferritin protects SH-SY5Y cells against H2O2-induced oxidative stress and modulates α-synuclein expression Exp. Neurol. 2017 291 51 61 10.1016/j.expneurol.2017.02.001 28163159 · DOI
  44. [44]Schultheis PJ Characterization of the P5 subfamily of P-type transport ATPases in mice Biochem. Biophys. Res. Commun. 2004 323 731 738 10.1016/j.bbrc.2004.08.156 15381061 · DOI
  45. [45]Podhajska A Common pathogenic effects of missense mutations in the P-type ATPase ATP13A2 (PARK9) associated with early-onset parkinsonism PLoS ONE 2012 7 e39942 10.1371/journal.pone.0039942 22768177 PMC3386943 · DOI
  46. [46]Abe K Irie K Nakanishi H Suzuki H Fujiyoshi Y Crystal structures of the gastric proton pump Nature 2018 556 214 218 10.1038/s41586-018-0003-8 29618813 · DOI
  47. [47]Dubey V K+ binding and proton redistribution in the E2P state of the H+, K+-ATPase Sci. Rep. 2018 8 12732 10.1038/s41598-018-30885-w 30143663 PMC6109069 · DOI
  48. [48]Bowman EJ Siebers A Altendorf K Bafilomycins: a class of inhibitors of membrane ATPases from microorganisms, animal cells, and plant cells Proc. Natl. Acad. Sci. USA 1988 85 7972 7976 10.1073/pnas.85.21.7972 2973058 PMC282335 · DOI
  49. [49]Wang R Molecular basis of V-ATPase inhibition by bafilomycin A1 Nat. Commun. 2021 12 1782 10.1038/s41467-021-22111-5 33741963 PMC7979754 · DOI
  50. [50]Vrijsen S ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress Proc. Natl. Acad. Sci. USA 2020 117 31198 31207 10.1073/pnas.1922342117 33229544 PMC7733819 · DOI
  51. [51]Cao Q BK channels alleviate lysosomal storage diseases by providing positive feedback regulation of lysosomal Ca2+ release Dev. Cell 2015 33 427 441 10.1016/j.devcel.2015.04.010 25982675 · DOI
  52. [52]Wang W A voltage-dependent K+ channel in the lysosome is required for refilling lysosomal Ca2+ stores J. Cell Biol. 2017 216 1715 1730 10.1083/jcb.201612123 28468834 PMC5461029 · DOI
  53. [53]Cang C Aranda K Seo Y-J Gasnier B Ren D TMEM175 is an organelle K+ channel regulating lysosomal function Cell 2015 162 1101 1112 10.1016/j.cell.2015.08.002 26317472 · DOI
  54. [54]Jinn S TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation Proc. Natl. Acad. Sci. USA 2017 114 2389 2394 10.1073/pnas.1616332114 28193887 PMC5338534 · DOI
  55. [56]Fujii T Survival of detached cancer cells is regulated by movement of intracellular Na+,K+-ATPase iScience 2021 24 102412 10.1016/j.isci.2021.102412 33997694 PMC8099779 · DOI
  56. [57]Fujii T K+-Cl- cotransporter-3a up-regulates Na+,K+-ATPase in lipid rafts of gastric luminal parietal cells J. Biol. Chem. 2008 283 6869 6877 10.1074/jbc.M708429200 18178552 · DOI

Cited by

Sorted by citations

Authors
Fujii, T., Nagamori, S., Wiriyasermkul, P., Zheng, S., Yago, A., Shimizu, T., Tabuchi, Y., Okumura, T., Fujii, T., Takeshima, H., & Sakai, H.
Affiliations
  • University of Toyama (JP)
  • Jikei University School of Medicine (JP)
  • Kyoto University (JP)
Corresponding author
  • Fujii, Takuto
  • Fujii, Tsutomu
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-04-20
Volume
14
Issue
1
Pages
2174-2174
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-37815-z
PMC
PMC10119128
OpenAlex
W4366549724
Cited by
72
References
1
Citations by year
2026: 30 · 2025: 22 · 2024: 15 · 2023: 5
FWCI
12.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by)
Funders
Japan Society for the Promotion of Science (21H03365, 22H02801, 22K06827, 23K24063, 20K07258)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
Keywords
ATP13A2, PARK9, Parkinson's disease, Kufor-Rakeb syndrome, lysosomal acidification, alpha-synuclein degradation, thapsigargin, vonoprazan, lysosomal alkalinization, ATPase inhibitors
MeSH terms
Proton-Translocating ATPases, Humans, Lysosomes, Mutation, Parkinson Disease, H(+)-K(+)-Exchanging ATPase, Parkinsonian Disorders, alpha-Synuclein

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